Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), kills more than 2 million people worldwide annually. M.bovis BCG, the only TB vaccine available, is of limited efficacy. The emergence of effectively untreatable extremely drug resistant (XDR) and multi-drug resistant (MDR) strains of Mtb underscores the requirement for an effective TB vaccine. Despite identification of several promising Mtb antigen vaccine candidates, our poor understanding of the requirements of early and effective memory responses to Mtb remains a significant challenge to the development of effective vaccine strategies. Interferon-gamma (IFN )-producing T helper 1(Th1) memory cells are required for effective protection against TB. However, we recently reported that an Interleukin (IL)-17-producing CD4+ T helper (Th17) memory cells are required for accumulation of Th1 memory cells and protective memory responses to Mtb challenge. We hypothesize that successful vaccination against TB requires Th17 memory cells. According to this hypothesis, vaccination with Mtb antigen results in the generation of antigen specific-Th17 and Th1 CD4+ cells, the Th17 cells being sequestered in the lung. Upon subsequent challenge with Mtb, lung resident Th17 memory cells proliferate rapidly, producing IL-17 and triggering the local expression of chemokines. We will test this hypothesis in three aims.
Aim 1 : Identifying the specific factors required for effective Th17 memory response following Mtb challenge.
Aim 2 : The mechanism by which Th17 memory cells mediate Th1 accumulation.
Aim 3 : To determine whether increasing the Th17 lung resident population improves vaccine- induced protection against TB. The work proposed in this grant will significantly impact the design of future vaccine strategies by allowing us to target IL-17 with the long-term goal of improving vaccine strategies against TB in humans.
Tuberculosis(TB), caused by the organism M.tuberculosis (Mtb) kills more than 2 million people worldwide every year. To improve immunization strategies against TB, it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will significantly impact the design of future vaccine strategies by allowing us to improve vaccine-induced Th17 responses to generate better vaccine-induced immunity against TB will therefore have the potential to reduce the incidence of TB.
|Ahmed, Mushtaq; Smith, Douglas M; Hamouda, Tarek et al. (2017) A novel nanoemulsion vaccine induces mucosal Interleukin-17 responses and confers protection upon Mycobacterium tuberculosis challenge in mice. Vaccine 35:4983-4989|
|Domingo-Gonzalez, Racquel; Das, Shibali; Griffiths, Kristin L et al. (2017) Interleukin-17 limits hypoxia-inducible factor 1? and development of hypoxic granulomas during tuberculosis. JCI Insight 2:|
|Ahmed, Mushtaq; Jiao, Hongmei; Domingo-Gonzalez, Racquel et al. (2017) Rationalized design of a mucosal vaccine protects against Mycobacterium tuberculosis challenge in mice. J Leukoc Biol 101:1373-1381|
|Treerat, P; Prince, O; Cruz-Lagunas, A et al. (2017) Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection. Mucosal Immunol 10:1069-1081|
|Griffiths, Kristin L; Villarreal, Daniel O; Weiner, David B et al. (2016) A novel multivalent tuberculosis vaccine confers protection in a mouse model of tuberculosis. Hum Vaccin Immunother 12:2649-2653|
|Gish, Stacey R; Maier, Ezekiel J; Haynes, Brian C et al. (2016) Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response. MBio 7:e00313-16|
|Domingo-Gonzalez, Racquel; Prince, Oliver; Cooper, Andrea et al. (2016) Cytokines and Chemokines in Mycobacterium tuberculosis Infection. Microbiol Spectr 4:|
|Griffiths, Kristin L; Ahmed, Mushtaq; Das, Shibali et al. (2016) Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy. Nat Commun 7:13894|
|Monin, Leticia; Griffiths, Kristin L; Lam, Wing Y et al. (2015) Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J Clin Invest 125:4699-713|
|Monin, L; Griffiths, K L; Slight, S et al. (2015) Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge. Mucosal Immunol 8:1099-109|
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